1. Field of the Invention
This invention relates to huperzine A and its derivatives, as well as their application as pharmaceutically-active analgesic agents.
2. Description of the Related Art
Chronic pain types include cancer pain, caused by the tumor pressing on bones, nerves, and other organs; nociceptive pain, caused by damage of tissues or organs; arthritic pain, caused by autoimmune response, such as inflammation (arthritis, gastritis, hepatitis); and neuropathic pain, especially migraine pain, caused by various abnormalities of the central nervous system.
Clinically, migraine pain features pulsating headache on one or both sides of the head, having duration of between 4 and 74 hours for each attack, and being simultaneously accompanied by symptoms of nausea, vomiting and photophobia. In certain patients specific premonitory symptoms, lasting about 10 to 20 min, such as visual symptoms of scotoma and light flash, numbness, and dizziness, may occur before the incidence of migraines.
With acceleration of the life styles and increase of work pressure, the incidence of migraines has been on the rise throughout the world. In fact, migraines constitute now the most common medical condition distressing modern people. For example, in China migraine affects 3%-5% of adult population, of which females are more susceptible than males by a factor of 3 to 4. In most cases, the onset of migraine occurs in adolescence.
In developed countries, the incidence of migraine is much higher. The statistics from the National Headache Foundation (USA) show that one of every ten people suffers from migraine headaches in USA, but more than half of the patients have not been even properly diagnosed. Similar data from the National Institute of Neurological Disorders and Stroke (NIH, USA) has revealed that there are 28 million patients with migraines in America and that migraine has caused an annual loss of about 157 million working days. Not surprisingly, pain management is one of the most common goals of homeopathy, and the treatment of migraine has become a hot medical field.
Conventional analgesics include two main types: opiate receptor ligands, with the typical example of morphine, which has strong analgesic effects but is prone to cause addiction; and non-narcotic analgesics, with the typical example of aspirin-derived paracetamol. There are also various new-generation analgesics having multiple mechanisms of action, conceived and manufactured successfully via modern processes for drug design, screening and development, which have weak analgesic effects, but which usually do not form dependence. Although some of these analgesics have serious side effects, e.g., they cause damage to the digestive tract, they are widely used and have an estimated combined market share of nearly 10 billion US dollars.
In the past twenty years, new types of 5-hydroxytryptamine (5-HT) antagonists and receptor stimulants have been identified in migraine effective treatment agents. Meanwhile, the development of analgesics acting on various targets of CNS has become a hot field in the new drug development area. However, most of these research objectives have focused on the 5-HT receptor and the dopamine receptor. Specifically, in the last 10 years, it was discovered that the 5-HT receptor and the dopamine receptors are divided into various subtypes, and the ability to interact with certain subtypes is related to analgesic effects of drugs, as well as the decrease or complete elimination of toxic and other side effects. This precipitated a great amount of research on these targets.
Acetylcholine, a neurotransmitter, was discovered much earlier than 5-HT. However, the acetylcholine receptor and acetylcholine esterase have not been popular targets for developing analgesic drugs. Nevertheless, in European Pat. No. EP 413667 A and U.S. Pat. No. 5,010,083, compounds used for treatment of both memory loss and relief of pain have been reported, which suggests that improvement of memory has some association with analgesia, and further reveals that increase in the level of acetylcholine may have analgesic action.
In addition, Stoyan once reported that the alkaloids nivalin and syntostigmine may alleviate migraine pain (Stoyan Iv Ikonomoff, Archives Suisses de Neurologie, Neurochirurgie et de Psychiatrie, Vol. 102, Fascicule, pages 299-312 (1968)). It was later found that these two compounds may inhibit activity of acetylcholine esterase. Because of a low inhibition activity of acetylcholine esterase or a low ability to permeate the blood-brain barrier, higher doses of these two compounds, and other acetylcholine esterase inhibitors subsequently tested, are required in order to provide therapeutic effects.
To achieve high concentrations, these compounds must be administered by injection. Hence, on one hand, the blood drug concentration is so high so as to have many side effects; on the other hand, the administration by way of injection is inconvenient. As a result, the research on acetylcholine esterase inhibitors used for treatment of migraine was put on hold. This was the first time when it was proposed that acetylcholine esterase inhibitors could be used for treatment of migraine.
The breakthrough in this field came from research and development of novel inhibitors of acetylcholine esterase. These novel inhibitors, such as donepezil, have high activity, highly-selectivity and easy permeation through the blood-brain barrier, so that they are able to overcome the shortcomings of the first generation of acetylcholine esterase inhibitors described above for the treatment of migraine. As disclosed in U.S. Pat. No. 6,608,088, donepezil was observed to have efficacy on migraine in clinical trials.
Huperzine A can inhibit acetylcholine esterase selectively, is easy to permeate through the blood-brain barrier, can promote memory reappearance and enhance memory maintenance. However, no literature reports have appeared that huperzine A may used for pain control, and especially the treatment of migraine.